1. Technical Field
The present invention relates generally to the technical field of methods for the controlled nucleation and growth of crystals. Particularly, the present invention relates to the technical field of methods for the crystallization of nanometer and micron-sized crystals. More particularly, the present invention relates to the technical field of fabricating crystals of molecular organic compounds while operating at a low supersaturation.
2. Prior Art
Crystallization from solution is an important separation and purification process in the chemical process industries. It is the primary method for the production of a wide variety of materials ranging from inorganic compounds, such as calcium carbonate and soda ash, to high value-added materials, such as pharmaceuticals and specialty chemicals. In addition to product purity, crystallization must also produce particles of the desired size and shape, as well as particles of the desired polymorph.
Chemical species have the ability to crystallize into more than one distinct structure. This ability is called polymorphism (or, if the species is an element, allotropism). Different polymorphs of the same material can display significant changes in their properties, as well as in their structures. These properties include density, shape, vapor pressure, solubility, dissolution rate, bioavailability, and electrical conductivity. Polymorphism is quite common among the elements and also in inorganic and organic species. It is especially prevalent in organic molecular crystals, which often possess multiple polymorphs. The incidence of polymorphism in organic molecular crystals bears great significance to the pharmaceutical, dye, agricultural, chemical, and explosives industries.
Under a given set of conditions, one polymorph exists as the thermodynamically stable form. This is not to say, however, that the other polymorphs cannot exist or form in these conditions. It means only that one polymorph is stable while the other polymorphs can transform to the stable form. For example, acetaminophen (the active ingredient in Tylenol(copyright)) can exist in two forms. The thermodynamically stable phase has a monoclinic form of space group P21/n. A second, less stable phase can be obtained; this phase is orthorhombic (space group Pbca) and has a higher density indicative of a closer packing of the molecules.
In pharmaceutical product development, the most stable polymorph has, generally, been selected for employment in the final dosage product. Yet in recent years, metastable forms have often been utilized due to their enhanced dissolution and/or bioavailability. In these cases, an understanding of the stability of these metastable forms under processing and storage conditions has proven crucial for the safety and efficacy of the drug. The United States Food and Drug Administration regulates both the drug substance and the polymorph for all crystalline pharmaceuticals and requires extensive studies of polymorph stability.
To develop the optimal delivery method for a particular drug in the pharmaceutical industry, there exist two very important factors. These include the control of particle (crystal) size and shape and the production of the correct polymorph. In recent years, an increased interest in new drug delivery systems has developed, turning attention to direct injection (intravenous) methods and inhalation. These methods necessitate precise control of particle size, shape, and polymorph produced. Direct inhalation requires particles in the 1-3 micron range while direct injection requires particles in the 100-500 nanometer range.
Many different techniques are employed for particle size reduction, such as supercritical fluid crystallization, impinging jet crystallization, milling, and spray drying. However, each technique has its drawbacks. For instance, milling requires heat and, as a result, the solid may thermally degrade. Spray drying, supercritical fluid based crystallization, and other crystallization-based methods are contingent on the creation of a very high supersaturation, thus favoring particle nucleation over growth. While effective in making small particles, high supersaturation often results in amorphous materials or an undesired polymorph, rather than the desired form of the crystalline compound. This is particularly true in the case of organic molecular crystals, in which the forces holding the molecules together in the lattice prove relatively weak.
Crystallization from solution begins with the nucleation of crystals followed by the growth of these nuclei to finite size. Nucleation and growth follow separate kinetic regimes with nucleation normally being favored at high driving forces (supersaturation) and growth being favored at low supersaturations. Since the ratio of the rate of nucleation to growth during a crystallization process determines the crystal size distribution obtained, this means that high supersaturations are normally employed to produce small crystals. In attempting to produce crystals in the 1-5 micron range and crystals below 1 micron, this has led to the use of methods that produce very large supersaturations such as supercritical fluid crystallization and crystallization from an impinging jet. Both of these methods suffer from significant problems. One problem is that substances that form organic molecular crystals can be difficult to nucleate under high supersaturations and often produce amorphous material instead of the desired crystals. Another problem is that these methods are difficult to control, design and scale-up and have had little commercial success. A third problem is that these methods can produce an undesired polymorph because of the high levels of supersaturation used.
Organic monolayer films have been used as an interface across which geometric matching and interactions, such as van der Waals forces and hydrogen bonding, can transfer order and symmetry from the monolayer surface to a growing crystal. Nucleation and growth of organic crystals, nucleation rates, polymorphic selectivity, patterning of crystal, crystal morphology, and orientation (with respect to the surface) can undergo modification through site-directed nucleation. This can be achieved using supramolecular assemblies of organic molecules, such as chemically and spatially specific surfaces. Compressed at the plane of water/air interface, Langmuir monolayers are mobilized by, and commensurate with, the adsorption of aggregates during crystallization.
Self-assembled monolayers (SAMs) are single layers of ordered molecules adsorbed on a substrate due to bonding between the surface and molecular head group. SAMs are molecular units that are spontaneously formed upon certain substrates, such as gold and silicon, when immersed in an organic solvent. One of the better known methods to form SAMs is when alkanethiol molecules chemisorb on gold surfaces through the thiol head group to reproducibly form densely packed, robust, often crystalline monolayer films. The surface chemical and physical properties of the monolayer films can be controlled precisely by varying the terminal chemical functionality of the alkanethiol molecule.
SAMs and mixed SAMs lack the mobility of molecules at an air-water, interface and, hence, lack the ability to adjust lateral positions to match a face of a nucleating crystal. This is especially true for SAMs of rigid thiols, for which even conformational adjustment is not possible. SAMs of 4-mercaptobiphenyls are superior to those of alkanethiolate in providing stable model surfaces, as well as in the ability to engineer surface dipole moments. Coupled with the ability to engineer surface functionalities at the molecular level, SAMs and mixed SAMs of rigid thiol offer unique surfaces for nucleation and growth of inorganic and organic crystals.
Silane SAMs have been used to promote heterogeneous nucleation and growth of iron hydroxide crystals and to study the effect of surface chemistry on calcite nucleation, attachment, and growth. For example, CaCO3 has been crystallized on surfaces of alkanethiolate SAMs on gold and SAMs of functionalized alkanethiols can control the oriented growth of calcite. Also, The heterogeneous nucleation and growth of malonic acid (HOOCCH2COOH) has occurred on surfaces of alkanethiolate SAMs on gold that terminated with carboxylic acid and with methyl groups. However, while SAMs have been used to grow crystals, specifically patterned SAMs have not been used to limit the dimensions and sizes of crystals, or to grow distinct crystal of selected dimensions and sizes.
Therefore, it can be seen that there is a need for a method for producing crystals of a desired structure and finite size while limiting the production of amorphous materials. There also is a need for a method for producing micron and nanometer scale crystals that is less difficult to control, design and scale-up. There is a further need for a method for the production of organic molecular crystals of controlled size in the 1-5 micron range and the 100-1000 nanometer range. There also is a need for a simple, efficient and effective controlled method for the production of small sized crystals.
Briefly described, the present invention is a novel route to producing small crystals and is based on the concept that such crystals can be produced using the modest supersaturations normally employed to crystallize most materials and controlling the crystal size by restricting the size and geometry of the crystallization domain. One example of a crystallization domain of controlled size and geometry is a self-assembled monolayer (SAM) with local domain area sizes selected to result in a crystal having the desired dimensions. Another example of a crystallization domain of controlled size and geometry is a capillary having a selected inner diameter for use as the crystallizer. More generally described, the present invention is a new process for the production of crystals of controlled size in the 1-5 micron and 100-1000 nanometer range by the use of a vessel geometry that limits the potential size of the crystals. The process is particularly suitable for the production of molecular organic crystals, but can be used to produce crystals from other types of compounds as well.
The present invention comprises at least two novel techniques for the crystallization of micron- and nanometer-size crystals of molecular organic compounds while operating at a low or modest supersaturation. Both methods are based on controlling the domain size available during the crystallization process, namely the crystallization vessel or equivalent (the crystallization domain). Both methods allow control of supersaturation and growth conditions, as well as manageability over crystallinity and polymorphism. Both methods domain size has the potential for further reduction, if necessary.
In a first method, the crystallization domain comprises microcontacted printed self-assembled monolayers (SAMs) with local domain area sizes ranging from 25 xcexcm2 to 2500 xcexcm2 and fabricated SAMs generated from electron beam (e-beam) lithography. These SAMs are employed to control-the size, orientation, phase, and morphology of the crystal. Functionalized SAMs can serve as heterogeneous nucleants and promote the nucleation of organic, inorganic, and protein crystals.
In a second method, the crystallization domain comprises a continuous micro-crystallizer, such as a capillary or other confined structure. In this instance, the vessel diameter (for example, the inner diameter of the capillary) preferably is 25 microns or less to ensure that that the maximum size of the crystals in two dimensions is constrained by the vessel itself. The mother solution is introduced into the capillary and supersaturation created by cooling or the addition of an antisolvent or both. Crystallization then occurs, but the crystal can grow no larger than the inner diameter of the capillary in two of its three dimensions because of the restrictions due to the capillary. The third dimension of the crystal can be controlled by the residence time of the solution in the capillary. Those of skill in the art know of and can develop other vessels for producing such crystals, and the present invention is not meant to be limited to the production of crystals in a capillary or in the example vessels disclosed above.
There are a myriad of uses for the crystals produced by the present process. One use for such crystals in the 1-5 micron range is for the production of pharmaceuticals for inhalation therapies. One use for such crystals in the submicron (100-1000 nanometer) range is for the production of pharmaceuticals for direct injection. Those of skill in the art know of and can develop other uses for such crystals, and the present invention is not meant to be limited to the production of crystals for the examples given above.
That the present invention improves over the current art and addresses the needs in the technical field will become apparent when the following detailed description of the preferred embodiments is read in conjunction with the appended figures, in which like reference numerals represent like components throughout the several views.